Endocrinologists weigh future of obesity management

During the past decade, the prevalence of obesity has climbed dramatically. Data show a 2.4 million increase between 2007 and 2009 in the number of US adults who are obese, and the epidemic shows no signs of stopping.

The past year was discouraging for weight-loss drugs. Three separate medications went before the FDA for approval — lorcaserin, phentermine plus topiramate, naltrexone plus bupropion — and all three were met with rejection. In addition, sibutramine, a weight-loss drug approved by the FDA more than a decade ago, was pulled from the US market because of safety concerns.

Many physicians who care for obese patients said the field of weight-loss drug development has been dealt a considerable blow.

“As a physician who cares for patients with obesity, it concerns me globally that once again it looks like we have a barrier toward getting safe and effective treatments for people with obesity,” Steven R. Smith, MD, scientific director of the Florida Hospital/Sanford-Burnham Translational Research Institute for Metabolism and Diabetes, said in an interview.

For Endocrine Today Editorial Board member, George A. Bray, MD, the recent FDA decisions, coupled with the dramatically increasing obesity epidemic, raise important questions about the future of pharmacologic treatment for obesity.

George A. Bray

“There is only one drug approved for long-term use — orlistat. Lifestyle is effective and safe, but preventing weight regain has been difficult. Surgery is effective, but carries risks,” Bray said. “There is a gap for safe and effective medications.”

Despite a prevailing sense of frustration, some endocrinologists harbor hope for the future. Smith said during the past 2 decades, researchers and physicians have learned an exceptional amount about the science of body weight regulation while investigating new treatments and, therefore, should not disregard the potential for other novel therapies.

“There is some hope on the horizon,” Caroline M. Apovian, MD, of Boston University School of Medicine, told Endocrine Today.

A growing epidemic

As obesity statistics skyrocket, the need for medically based obesity treatments increases.

To illustrate this point, Donna Ryan, MD, of the Pennington Biomedical Research Center in Baton Rouge, La., cited a “very important” 2010 study that examined decade trends using National Health and Nutrition Examination Survey data from 1999 to 2006 compared with 2007 to 2008. Katherine M. Flegal, PhD, and colleagues at the CDC found that the age-adjusted prevalence of obesity in recent years was 33.8%, and results also indicated that 6.2% of the US population has a BMI of at least 40.

Katherine M. Flegal

“This is a burden of disease that we are going to face in the future that is going to demand more medical approaches,” Ryan said in an interview. “There is no way that we can ignore or deliver surgery to 6.2% of the population.”

Additionally, obesity places a significant burden on the health care system. Recent CDC estimates of the annual medical costs of obesity are as high as $147 billion, with averages suggesting that obese Americans have medical costs that are more than $1,400 than those people of average weight.

“More than 50 illnesses are caused by obesity,” Louis Aronne, MD, FACP, clinical professor of medicine at Weill Cornell Medical College, said in an interview. “If we are going to have an impact, we need to start thinking about obesity in a different way.”

Robert Kushner, MD, said it may be important to look at obesity as an underlying cause of disease as opposed to a separate health problem. Preventing and treating obesity could considerably cut costs associated with the disease, as well as potentially replace medications used for other related illnesses such as diabetes and cardiovascular disease.

“The irony is there are medications for every one of these comorbid conditions — of which obesity causes or worsens — but there isn’t a single medication that’s approved other than phentermine and over-the-counter orlistat to treat obesity,” said Kushner, professor of medicine at the Feinberg School of Medicine, Northwestern University.

Current armamentarium

According to most physicians, diet and exercise are the cornerstones of weight-loss management; however, adherence issues are troublesome.

Nevertheless, currently available medications have not fared much better for various reasons. Phentermine, which was approved in 1959 for 3-month use, has not undergone any long-term clinical trials since its approval, and any use longer than 3 months is considered off-label. Orlistat (Xenical, Hoffmann-La Roche; Alli, GlaxoSmithKline) is approved for long-term use, but studies only link the drug to an extra 2.9% loss in body weight when compared with placebo. Bariatric surgery induces more weight loss but is considered an extreme method with varying long-term results.

In February, the FDA approved a lower indication for Allergan’s adjustable gastric banding system (Lap-Band). Now, adults who have a BMI between 30 and 40 and at least one obesity-related comorbid condition are eligible for the procedure. Since its approval in 2001, Allergan estimates that more than 300,000 people worldwide have the Lap-Band.

“It is interesting to me that another surgical device was approved for a lower BMI indication before we have another weight-loss drug out there,” Apovian said.

Aronne likened it to “an era where people are going to be going from Weight Watchers to the operating room.” He said surgery is clearly effective, but most patients would prefer trying medical options first.

Physicians are not the only ones feeling the pressure, according to Smith.

Steven R. Smith

“Patients are literally dying for some kind of therapy. The treatment gap in between [the currently available options] is huge, and patients recognize it,” he said.

Benefits, limitations of therapy

The overarching question is: Could a new weight-loss pill curb the growing obesity epidemic? The answer remains complex, but physicians said having one more tool in the toolbox will help them make a dent by allowing them to tailor treatment to the individual.

“Obesity is not one condition; it’s like cancer. There are multiple cancers, there are multiple drugs for cancer, and the type of cancer a patient has dictates the course of treatment you embark upon,” Kushner said. “Obesity is very similar.”

Louis Aronne

Why would a pill succeed where diet and exercise have failed? A drug can help increase adherence by mitigating some of the biological and genetic factors contributing to obesity in certain patients, according to Aronne. For instance, a pill can alleviate cravings, aid patients in exercising greater control over their eating habits and, in some cases, boost the amount of calories burned off through the sympathetic system.

“Evidence indicates that obesity is a disorder of neuroendocrine regulation,” Aronne said. “Leptin resistance is probably one of the central mechanisms, and even though we can’t get at that yet, we can work around it.”

Additionally, initial weight loss prompted by a pill may make exercising easier for some obese patients by relieving stress on their knees, hips and back, according to Smith.

“They actually have a greater capacity for physical activity after losing weight. They feel better and are more capable,” he said.

Moreover, most obese patients who have struggled with adherence to lifestyle changes because of frustration for not seeing results may find motivation in actually experiencing the benefits of weight loss for the first time.

“The strongest motivation for behavior change is success. If a patient does not see success, he or she is not likely to follow the recommendations,” Kushner said. “If the medication is going to augment or amplify the success rate, including how much weight a patient loses, he or she is more likely to be incentivized to continue with diet and exercise recommendations.”

Robert Kushner

Nevertheless, as with all treatments, medications have shortcomings. Obvious downsides are potential adverse effects. This problem, however, is not unique to weight-loss drugs and is easily addressed by judicious use and comprehensive patient and physician education, Kushner said. Careful observation of patient response is essential.

Emphasizing that a pill is a supplement to lifestyle modifications, not a panacea, is also important, Aronne said, noting that, in the past, physicians prescribing weight-loss medications were not always responsible, and these drugs were viewed as a “magic solution” rather than an ancillary treatment. Yet, endocrinologists are positioned to prevent this problem from reoccurring.

“Endocrinologists, in my opinion, are a perfect group of people who can play an important role in a team managing weight problems,” he said. “Endocrinologists need to play a leading role in the same way that infectious disease doctors played leading roles when HIV first appeared.”

Examining risks, overall weight loss

Concerns about adverse events associated with the investigational drugs up for approval in 2001 and 2010 took center stage at the FDA meetings.

The panels discussed data that linked lorcaserin (Lorqess, Arena Pharmaceuticals) to mammary tumors, mammary adenocarcinoma and brain astrocytoma. Combination phentermine plus topiramate (Qnexa, Vivus) met similar resistance because of links to psychiatric and cognitive events, teratogenicity, metabolic acidosis and major CV events. Although naltrexone plus bupropion (Contrave, Orexigen) received recommendation for approval from an FDA advisory committee, the agency ultimately viewed the risks for elevated blood pressure as outweighing the drug’s benefits. Finally, sibutramine (Meridia, Abbott Laboratories) was removed after 10 years of market availability after data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial linked the drug to major CV events, including nonfatal myocardial infarction and stroke.

The amount of weight loss associated with obesity medications has been scrutinized as well. For example, the investigational naltrexone/bupropion combination reportedly induced a modest 5% body-weight reduction — a number that has increased to 8% in later trials — as compared with placebo.

Some said, however, that these data do not denote a significant benefit in terms of weight loss.

“These are averages,” Kushner said. “An average is a statistical analysis, but patients don’t respond as an average; they respond as individuals.”

Therefore, he said efficacy data should be interpreted in terms of responders and nonresponders. With each medication, clinical trials demonstrated that certain populations lost at least 10% of their body weight, and those are the ones for which treatment would be appropriate.

Most experts agree that one drug will not work for everyone, a reason why approval of more treatments in the weight-loss toolbox is important.

“This is how we manage hypertension; we need to start doing this with obesity. One drug isn’t going to do it. There are multiple pathways going to the brain. The desire to eat is linked to survival; we can’t just knock out one path; another path is going to come in and take over,” Apovian said.

Aronne said if 10 drugs were available for weight loss, such as with hypertension, patients would most likely be able to eat better and maintain their overall weight loss.

Donna Ryan

“If a patient is taking BP medicine and their BP is not going down, then you switch to a different category [of medication],” Aronne said. “But with BP medicine, there are a hundred drugs in nine different categories. Unfortunately, we are not in that situation.”

Part of the problem with getting new drugs approved is that investigational weight-loss drugs are not positioned for medical intervention, according to Ryan.

“The FDA panelists who reviewed the drug tended to view obesity as a cosmetic problem. One panelist even compared obesity drugs to Latisse (bimatoprost, Allergan), a treatment designed to make eyelashes grow,” she said. “Weight loss needs to be taken more seriously.”

Click here to view a timeline on the brief history of weight-loss drugs in the US.

Bridging the gap

Until the medical gap between diet and exercise and surgery is filled, physicians are becoming more resourceful with weight-loss management.

“We have to be creative and think out of the box,” Apovian said. In some cases, this means using medications off-label, even drugs that are not currently indicated for weight-loss management.

“At my clinic, the patients come to us because they know we will try whatever we can to help them lose weight,” including topiramate, phentermine, naltrexone, bupropion, pramlintide (Symlin, Amylin), exenatide (Byetta, Amylin) and metformin.

Smith said he too started looking at diabetes drugs in a way that allows him to initiate therapy for prediabetes and hyperglycemia in a way that is “weight-centric as opposed to glycemic-centric.”

Aronne said physicians should be aware of managing other medications that may be linked to additional weight gain for obese patients.

“The typical patient I see is taking seven or eight medicines. Often, they’ll be taking a medicine that may cause them to gain weight. If we get rid of one or two of those medications, that may help them to lose more weight through diet and exercise,” Aronne said.

Some diabetes drugs are entering clinical trials that will examine effects on weight loss. Two primary examples are liraglutide (Victoza, Novo Nordisk) and exenatide. According to a 2009 study published in The Lancet, varying doses of liraglutide were associated with mean weight losses of 1.2 kg to 7.2 kg, and 76% of thecohort lost more than 5% of their body weight with 3 mg of liraglutide compared with placebo (30%) and orlistat (44%). Similarly, a 2010 study, also published in The Lancet, indicated that weight loss with exenatide was significantly greater than weight loss with sitagliptin (Januvia, Merck) or pioglitazone (Actos, Takeda).

“Certainly, many endocrinologists are probably using this preliminary pilot data to use these drugs for weight loss,” Kushner said.

On the horizon

In light of the recent FDA decisions, many are uneasy about the future of obesity drugs. However, the outlook is not completely bleak.

“These drugs are still in the running,” Ryan said. “They are down, but they are not out.”

She said combination phentermine plus topiramate seems to be the most promising obesity drug. However, the future for other drugs in the current pipeline seems less positive. The FDA requested a large-scale, multicenter, randomized, CV-endpoint trial for Contrave, which will cost Orexigen millions of dollars. Because of this, and other similar instances, some question the ability of the company to proceed financially.

Nevertheless, there is hope as other approaches populate the pipeline.

“There is continuing emphasis on trying to identify targets for developing drugs that could treat obesity through nontraditional approaches,” Smith said, noting that they differ from most of the current efforts, which have targeted neural receptors and pathways to reduce food intake.

Ryan said there have been great advances in understanding the biology and energy balance that underlie obesity.

“Even surgery has reinforced the importance of gut peptides in appetite regulation and weight loss. There are many avenues to pursue: gut peptides; leptin; renewed interest in brown fat,” she said.

Additionally, other research has focused on naturally occurring hormonal systems, shifting the focus way from the central nervous system as the target organ for obesity treatment, according to Smith.

Apovian said she remains positive about investigational injectable compounds. She and colleagues are conducting early trials on the roles of leptin and pramlintide in obesity. Although final results are still a few years away, it appears that weight loss may exceed 12%. Because leptin is an adipocyte hormone and pramlintide a pancreatic hormone, the adverse effect profile is “excellent” and without CV issues, she added.

“I think of the treatment gap like this: We’re going to fill it,” Smith said. “It may take a long time, but we have to stay the course and recognize that we can be smarter about it.”

He said hypertension drugs are an example of why he remains so optimistic, despite the present climate.

“To me, there is a pro-research and dig-deep-into-the-biology message here because the knee-jerk is to say, ‘We failed, let’s stop,’” Smith said. “If you told somebody that about hypertension in 1975, they would have maybe felt the same way, but look where we are now. It’s a more hopeful message based upon the reality of the history that we have with hypertension, with oncology, with a variety of other endocrine areas where we’ve made great strides based on science.” – by Melissa Foster and Katie Kalvaitis

For more information:

• Astrup A. Lancet. 2009;374:1606-1616.
• Bergenstal RM. Lancet. 2010;376:431-439.
• CDC. MMWR. 2010;59:1-5.
• Flegal KM. JAMA. 2010;303:235-241.

Do you consider obesity a disease?

Genetic causes, adverse outcomes characterize obesity as disease

Obesity has defining elements of a disease: a genetic component, morbid consequences and, at one time, it was an adaptive feature.

The best analogy would be sickle cell anemia. Here is a disease of the red blood cell that is genetic, has morbid outcomes and used to be protective against malaria infections. This adaptation, however, is no longer needed in areas where malaria is not a public health threat, such as North America. Therefore, in an area without malaria, the disease has no adaptive function and instead causes severe problems.

Ken Fujioka

Obesity works in the same way. Biologically, obesity has a clear pathway related to genetics. For example, if both parents are obese, then their child has an 80% to 90% chance of being obese, whereas if neither parent is obese, the child’s odds of being obese are substantially lower. Environmental, social and behavioral factors, however, remain contributors in some cases, regardless of genetics.

The morbid consequences of obesity include health problems, such as diabetes, hypertension and CVD. One thing that physicians might want to remember is that it has clearly been shown that if you resolve these other health issues, such as high blood pressure and cholesterol, obese patients are still at a higher risk for heart disease.

What’s more is that obesity began as an adaptive feature. Currently, we are in a classic genetic mismatch where our genetics were set up to survive times of famine. However, we no longer have that problem in the United States and other more developed countries that are doing well and have a constant food supply. Therefore, genetics are now working against us. People who are already predisposed to obesity now gain weight more easily when compared with others whose genetics make it more difficult.

Ken Fujioka, MD, is director of the Nutrition and Metabolic Research Center and the Center for Weight Management at Scripps Clinic in La Jolla, Calif.

No strong association between obesity, other health conditions yet

Is obesity a disease? It is a question of how you ask the question. A disease, from the point of view of clinicians and health care providers, is an entity that generally causes signs or symptoms. Many obese patients have diabetes or hypertension, or signs of disease, but then there are some people with a lot of adiposity who are seen in clinics and have no complaints or symptoms.

Peter W.F. Wilson

Additionally, obesity may not always be present at or near the onset of other diseases, such as diabetes and hypertension. A person may have been obese at one point in his or her life, but may have lost the weight by the time he or she develops these other conditions. Furthermore, obesity may not need to be tremendous to contribute to the development of other diseases. Therefore, these issues make it difficult to determine a strong association between obesity and subsequent health problems.

Another problem with finding a robust relationship between obesity and other diseases is a lack of aggressive interventions for treatment of obesity. If there were aggressive interventions that show that reducing adiposity in adult years lowers risk of these adverse outcomes, then evidence that obesity is a disease would be more compelling. Obesity may in fact be soundly linked to conditions such as CVD, but without a potent treatment strategy involving a combination of lifestyle changes and pharmacology some clinicians will believe that evidence that adiposity is related to these outcomes is not overwhelmingly convincing.

However, obesity may still be considered a disease, even if not at this point in time. Some physicians and researchers make the point that with chronic conditions such as obesity, clinicians should be examining the long-term factors as well as the short-term causes contributing to related health conditions, such as CVD. Moreover, once more potent interventions for obesity are established, we will be able to learn more about it as a disease.

Peter W.F. Wilson, MD, is a professor of medicine in the cardiology division at Emory University School of Medicine. He is also an Endocrine Today Editorial Board member.

Disclosures: Dr. Apovian is a paid consultant for Arena Pharmaceuticals, Orexigen and Vivus. Dr. Aronne is a paid consultant for Amylin, Allergan, GlaxoSmithKline, Novo Nordisk, Orexigen and Vivus. Dr. Fujioka is a paid consultant for Abbott, Orexigen and Vivus. Dr. Kushner is on the advisory board for Orexigen and Vivus. Dr. Ryan reports no relevant financial disclosures. Dr. Smith is a consultant for Amylin and Arena Pharmaceuticals, and has received research support from Orexigen. Dr. Wilson reports no relevant financial disclosures.